This grant application is to support a study of the long-term effects on corneal transparency of the two most common surgical procedures on the central cornea in the U.S., corneal transplantation and excimer laser refractive surgery, the former to restore useful vision to abnormal corneas and the latter to eliminate the need for glasses or contact lenses in otherwise normal corneas. In previous studies we identified in long-term corneal transplants a loss of transparency called "late endothelial failure" that causes over 90% of graft failures after 5 years. These grafts have greatly decreased numbers of endothelial cells, keratocytes, and nerves, and the loss of transparency in late endothelial failure is associated with insufficient keratocytes rather than purely endothelial decompensation. In recent studies we found that after laser refractive surgery corneas had conditions in part similar to those of the transplanted corneas, i.e., decreased anterior keratocytes and nerves, for at least 3 years (our longest follow-up). The long-term effects of these keratocyte and nerve deficits after laser refractive surgery are of concern and have not been studied. This research plan will investigate the long-term effects of these cellular and nerve deficits on the human cornea: changes in corneal transparency that produce late endothelial failure after corneal transplantation, and potential long-term changes in corneal transparency and topography after laser refractive surgery. These will necessarily be clinical studies. We plan to study 100 patients (20 per year) with long-term corneal transplants. We will also study 20 patients after photorefractive keratectomy (PRK), 20 patients after laser-assisted in situ keratomileusis (LASIK), and 20 age-matched control patients, all for 4 years. For effects 5-9 years after surgery, we will study 15 PRK and 15 LASIK patients from our past investigations at 5, 7, and 9 years after surgery. We will also investigate in the laboratory new methods to prevent or delay late endothelial failure by using human corneas ex vivo. One central theme guides our research endeavors: The pathophysiologic effects of surgery on the central cornea can be discovered by careful prospective observation. Knowledge of these effects will lead to improvements in these surgical procedures.